798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update
Open accessAbstract
Background T-cell targeting of mutation-derived epitopes (neoantigens) has shown to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. mRNA-4157 is a lipid encapsulated mRNA based personalized cancer vaccine encoding neoantigens selected using a proprietary algorithm to induce neoantigen specific T cells and associated anti-tumor responses. This report includes updates from the mRNA-4157 Phase1(P1) study. The initial data was presented at ASCO2019.1 Methods This study evaluates the safety and efficacy of mRNA-4157 as monotherapy in patients with resected solid tumors (Part A) and in combination with pembrolizumab in patients with advanced/metastatic solid tumors (Parts B). The selected solid tumors in Part A-B includes melanoma, bladder carcinoma, HPV-negative (HPV-neg) HNSCC, NSCLC, SCLC, MSI-High (MSI-h), or TMB-High cancers. Expansion cohorts includes patients with CPI-naïve MSS-CRC and HPV-neg HNSCC (Part C) and with resected melanoma (Part D). Patients receive up to 9 cycles (Q3W) of mRNA-4157 by intramuscular injection at up to 1 mg alone (Part A) or in combination with pembrolizumab (200 mg IV Q3W, Parts B-D). Pembrolizumab is administered for two cycles before the first dose of mRNA-4157 and may continue after 9 cycles of combination. Endpoints include safety, tolerability, efficacy and biomarker assessments. Results 79 patients received mRNA-4157; 16 as monotherapy and 63 in combination with pembrolizumab. Only low grade and reversible treatment related AEs were reported. 14/16 Part A patients (3 melanoma, 11 NSCLC, 2 MSI-h CRC) remained disease free on study. 28 patients in Parts B (6 bladder, 2 HNSCC, 3 melanoma, 10 NSCLC, 2 SCLC, 4 MSI-h tumor, 1 TMB-h tumor), 27 patients in Part C (10 HNSCC and 17 MSS-CRC), and 8 patients with resected melanoma (Part D) received combination. 3 CR (1 HNSCC, 1 MSI-h CRC and 1 MSI-h prostate), and 8 PR (1 bladder, 4 HNSCC, 2 SCLC and 1 MSI-h endometrial) were observed with combination. Of 10 CPI-naïve HPV-neg HNSCC patients, the response rate was 50% (1CR, 4PR, 4SD) mPFS 9.8months, which compared favorably to published rates of ~14.6% mPFS 2.0months for pembrolizumab monotherapy.2 3 Biomarker assessments including immune gene expression profiling will be presented. Conclusions mRNA-4157 has an acceptable safety profile along with observed clinical responses in combination with pembrolizumab. Preliminary efficacy analysis from CPI-naïve relapsed/refractory HPV-neg HNSCC cohort suggests activity of this combination. Study is ongoing. Trial Registration NCT03313778 Ethics Approval The study was approved by each participating sites’ local IRB. References Burris H, et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. Journal of Clinical Oncology20 May 2019;37(15):2523-2523. Seiwert T, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17:956–65. Cohen E, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 2019;393:10167:156-16.
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In the combination group of a phase I study of mRNA-4157, the overall response rate in the cohort (human papillomavirus-negative, immune checkpoint inhibitor-naive, head and neck squamous cell carcinomas) was 50% and the median progression-free survival was 9.8 months.
“In the combination group, the overall response rate in the cohort (human papillomavirus-negative, immune checkpoint inhibitor-naive, head and neck squamous cell carcinomas) was 50% and the median progression-free survival was 9.8 months210,211.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [210]
mRNA-4157 is a personalized cancer vaccine encoding up to 34 neoantigens.
“For example, mRNA-4157 is a personalized cancer vaccine encoding up to 34 neoantigens210,211.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [210]
Several personalized cancer vaccines using lipid nanoparticle-mRNA formulations have entered clinical trials.
“Several personalized cancer vaccines using lipid nanoparticle–mRNA formulations have also entered clinical trials210–212.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [210]
In the monotherapy group of a phase I study of mRNA-4157, 14 out of 16 patients remained disease-free during the study, with a median follow-up time of 8 months.
“In the monotherapy group, 14 out of 16 patients remained disease-free during the study, with a median follow-up time of 8 months210,211.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [210]
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- Authors
- Bauman, J., Burris, H., Clarke, J., Patel, M., Cho, D., Gutierrez, M., Julian, R., Scott, A., Cohen, P., Frederick, J., Robert-Tissot, C., Zhou, H., Mody, K., Keating, K., Meehan, R., & Gainor, J.
- Affiliations
- University of Arizona (US)
- Sarah Cannon (US)
- Duke University (US)
- Florida Cancer Specialists & Research Institute (US)
- New York University (US)
- Hackensack, Hackensack, NJ, USA
- Moderna, Tenafly, NJ, USA
- Massachusetts General Hospital (US)
- ORCID
- Venue
- Late-breaking abstracts
- Publisher
- BMJ Publishing Group Ltd
- Published
- 2020-11
- Pages
- A477.1-A477
- OpenAlex
- W3099374672
- Cited by
- 54
- References
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- Citations by year
- 2026: 3 · 2025: 11 · 2024: 12 · 2023: 12 · 2022: 10 · 2021: 5 · 2020: 1
- Type
- conference abstract
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- personalized cancer vaccines, neoantigens, pembrolizumab, immune checkpoint inhibitors, combination immunotherapy, solid tumors, melanoma, non-small cell lung cancer, lung squamous cell carcinoma, bladder cancer, head and neck squamous cell carcinoma, microsatellite instability-high, tumor mutational burden, safety and tolerability, immunogenicity
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